Delivery of therapeutic agent to the respiratory tract is important for both local and systemic treatment of disease. With the conventional techniques, delivery of agents to the lung is extremely inefficient. Attempts to develop respirable aqueous suspensions of poorly soluble compounds have been unsuccessful. Micronized therapeutic agents suspended in aqueous media are too large to be delivered by aerosolized aqueous droplets. With conventional processes, it is estimated that only about 10 to 20% of the agent reaches the lung. Specifically, there is loss to the device used to deliver the agent, loss to the mouth and throat and with exhalation. These losses lead to variability in therapeutic agent levels and poor therapeutic control. In addition, deposition of the agent to the mouth and throat can lead to systemic absorption and undesirable side effects.
The efficiency of respiratory drug delivery is largely determined by the particle size distribution. Large particles (greater than 10 m) are primarily deposited on the back of the throat. Greater than 60% of the particles with sizes between 1 and 10 m pass with the air stream into the upper bronchial region of the lung where most are deposited. With particles less than about 1 μm, essentially all of the particles enter the lungs and pass into the peripheral alveolar region; however, about 70% are exhaled and therefore are lost.
In addition to deposition, the relative rate of absorption and rate of clearance of the therapeutic agent must be considered for determining the amount of therapeutic agent that reaches the site of action. Since 99.99% of the available area is located in the peripheral alveoli, rapid absorption can be realized with delivery of the particles to the periphery. For clearance, there is also differences between the central and peripheral regions of the lung. The peripheral alveolar region does-not have ciliated cells but relies on macrophage engulfment for particle clearance. This much slower process can significantly extend the time during which the particles reside in the lung thereby enhancing the therapeutic or diagnostic effect. In contrast, particles deposited in the upper respiratory tract are rapidly cleared by mucociliary escalator. That is, the particles are trapped in the mucous blanket coating the lung surface and are transported to the throat. Hence, this material is either swallowed or removed by coughing.
While it has long been known that smaller droplets of an aerosol reach deeper into the respiratory system (Current Concepts in the Pharmaceutical Sciences: Dosage and Bioavailability, J. Swarbrick Ed., Lea and Febiger, Philadelphia, Pa., 1973, pp. 97-148) these have largely been of theoretical interest. Simply knowing that smaller droplets of aerosol can be delivered deeper into the respiratory system does not solve the problem of incorporating sufficient therapeutic agent into the aerosol to be efficient, particularly where the therapeutic agent is only slightly soluble in the liquid for the aerosol.
Nanoparticles, described in U.S. Pat. No. 5,145,684, are particles consisting of a poorly soluble therapeutic or diagnostic agent onto which are adsorbed a non-crosslinked surface modifier, and which have an average particle size of less than about 400 nanometers (nm). However, no mention is made of attempts to nebulize (aerosolize or atomize are equivalent terms for the purpose of this disclosure) these compositions and it is not apparent that nebulizing these composition would provide useful aerosols or that there would be any advantage for doing so.